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Biomedical subjects

T J Regan

Publications and source records attributed to T J Regan.

At least 91 records · Page 5Linked to original sources
PubMed1977

The effects of tolbutamide on the myocardium in experimental diabetes.

The effects of chronic tolbutamide treatment were examined in a diabetic animal model in which abnormal myocardial function and composition have previously been demonstrated. Eight diabetic dogs were given tolbutamide 250 mg/day orally and compared with seven untreated diabetics, five healthy dogs receiving tolbutamide, and eight normal controls. After one year, resting hemodynamic studies in the intact anesthetized state showed that treated diabetic dogs had a significantly higher left ventricular end-diastolic pressure of 12.1+/-1.3 mm Hg associated with normal end-diastolic volume, compared to 6.1+/-0.8 mm Hg in untreated diabetics (P less than 0.01) and 6.3+/-0.5 in normals. Stroke work and ejection fraction were similar to normals. Acute volume expansion revealed a larger rise of left ventricular end-diastolic pressure in treated and untreated diabetics than normals, without a significant stroke volume response in treated diabetics. Enhanced stiffness of myocardium appeared to be related to interstitial accumulation of periodic acid-Schiff staining material, further intensified in treated diabetics by triglyceride accumulation observed on electron microscopy and by chemical analysis. Thus treatment of diabetes with tolbutamide, despite improved glucose tolerance, effected further reduction of left ventricular function and altered morphology of myocardium.

Animals↗
PubMed1977

Myocardial function and coronary blood flow response to acute ischemia in chronic canine diabetes.

To examine the influence of preexistent diabetes mellitus on left ventricular performance and coronary blood flow responses to acute ischemia, mild normoglycemic diabetes was induced in nine mongrel dogs after three doses of alloxan, (20 mg/kg, iv), at monthly intervals. Hemodynamic measurements and coronary blood flow (85Kr clearance) were obtained before and after the onset of ischemia. This was produced by occlusion of the proximal left anterior descending coronary artery via a balloon-type catheter in nine intact anesthetized diabetic dogs and 10 nondiabetic dogs. During the 1st hour of ischemia in the diabetic group, the end-diastolic pressure rose from 7 +/- 1.1 (mean +/- SE) mm Hg to 23.8 +/- 2.3 without a significant increase of end-diastolic volume. In controls end-diastolic pressure rose from 8.6 +/- 1.1 mm Hg to 15.3 +/- 1.4, and end-diastolic volume was significantly increased, so that the ratio of end-diastolic pressure and volume was significantly higher in the diabetic group (P less than 0.005). Although indices of contractility did not differ, stroke volume and work reductions were significantly greater in diabetics, despite the fact that coronary blood flow was reduced to a similar extent. Size of the ischemic areas appeared comparable as judged by distribution of dye injected distal to the occlusion. Since potassium loss and sodium gain in the inner and outer layers of ischemic tissue did not differ between the two groups, the intensity of ischemia seemed similar. Glycogenolysis was unimpaired in the diabetic ischemic muscle but triglyceride levels remained elevated. Morphologically the diabetic myocardium was characterized by a diffuse accumulation of periodic acid-Schiff-positive glycoprotein in the interstitium, which was thought to limit diastolic filling of the ischemic ventricle and to contribute to the substantial reduction of ventricular performance.

Animals↗
PubMed1977

Origin of acetyl strophanthidin-induced ventricular arrhythmias.

To examine the origin of digitalis-induced ventricular tachycardia (VT), acetyl strophanthidin (AS) (25 mug/min) was perfused into a limited zone of myocardium in intact anesthetized dogs through a catheter placed fluoroscopically in the left anterior descending artery without ischemia. A second catheter in the great cardiac vein sampled venous effluent from this region. His and left bundle branch depolarizations were recorded and bipolar intramural electrograms from endocardial and epicardial sites within the anterior descending region were obtained. No conduction alterations preceded arrhythmia. Cardiac venous K+ rose from 3.3 +/- to 4.4 +/- 0.2 meq/liter (P less than 0.001), indicating egress from the perfused zone. 10 animals (Group 1) were sacrificed 2 min after onset of VT while 11 (Group 2) continued until fibrillation (4-14 min). All showed normal (endocardial leads to epicardial) transmural depolarization during sinus rhythm, but 10/21 demonstrated reversal, usually late during VT, including 8/11 in Group 2. Epicardial activation preceded fascicular activation and QRS. Recordings from the border and circumflex regions in 10 additional dogs (Group 3) demonstrated activation reversal only in the border zone. Myocardial K+ was reduced (mean 63 +/- 1 mueq/g) and Na+ increased (mean 41 +/- 2 mueq/g) in the perfused zone (nonperfused circumflex area K+ 72 +/- 1, Na+ 33 +/- 1 mueq/g, P less than 0.001 for both); changes were similar in inner and outer ventricular wall. In related experiments, subepicardial injections of AS induced activation reversal within the immediate area, similar to recordings during coronary infusion. Reversed transmural activation with early epicardial depolarization suggest VT arises within myocardium; electrolyte gradients between adjacent regions may be causative.

Animals↗
PubMed1977

Evidence for cardiomyopathy in familial diabetes mellitus.

Recent epidemiologic studies have suggested that cardiac disease in common in diabetics and may often have a noncoronary basis. To examine the status of the left ventricle, 17 adult-onset diabetics of familial type without hypertension or obesity underwent hemodynamic study and were compared to 9 controls of similar age. Of the 17, 12 subjects had no significant occlusive lesions by coronary angiography. From this group eight without heart failure had a modest, but significant, elevation of left ventricular end-diastolic pressure. End-diastolic and stroke volumes were reduced, but ejection fraction and mean rate of fiber shortening were within normal limits. The left ventricular end-diastolic pressure/volume ratio was significantly higher than controls. Afterload increments effected a significant increase of filling pressure compared to normals without a stroke volume response, consistent with a preclinical cardiomyopathy. Four patients with prior heart failure had similar but more extensive abnormalities. None had local dyskinesia by angiography, and lactate production was not observed during pacing-induced tachycardia. Left ventricular biopsy in two patients without ventricular decompensation showed interstitial collagen deposition with relatively normal muscle cells. These findings suggest a myopathic process without ischemia. Postmortem studies were performed in 11 uncomplicated diabetics. Nine were without significant obstructive disease of the proximal coronary arteries, and the majority succumbed with cardiac failure. On left ventricular sections, none had evident luminal narrowing of the intramural vessels. All nine exhibited periodic acid-Schiff-positive material in the interstitium. Collagen accumulation was present in perivascular loci, between myofibers, or as replacement fibrosis. Multiple samples of left ventricle and septum revealed enhanced triglyceride and cholesterol concentrations, as compared to controls. Thus, a diffuse extravascular abnormality may be a basis for cardiomyopathic features in diabetes.

Adult↗
PubMed1976

Myocardial ischemia and cell acidosis: Modification by alkali and the effects on ventricular function and cation composition.

Myocardial cell pH was measured with 5, 5 dimethyl-2, 4-oxazolidinedione (DMO) in intact anesthetized dogs by a transient indicator dilution technique. Bolus injections of labeled DMO, vascular, extracellular and water indicators were made into the left anterior descending coronary artery, and blood samples were collected from the great cardiac vein. The steady state distribution of DMO between cells and plasma was calculated from the mean transit times of the indicator. Normal myocardial cell pH averaged 6.94 and changed by 58% of the concomitant alterations in plasma pH after infusions of acid or alkali. Myocardial ischemia induced by inflation of a balloon tip catheter in the left anterior descending coronary artery resulted in progressive decreases in cell pH to 6.59 by 1 hour. Infusions of sodium carbonate diminished intracellular acidosis. Hemodynamic studies during 4 hours of ischemia with blood pH at 7.55 to 7.60 indicated a significantly reduced left ventricular end-diastolic pressure and increased stroke volume by comparison with findings in animals given infusions of saline solution. Ventriculograms revealed improved wall motion in the ischemic segment after infusion of alkali. Precordial mapping showed a significant reduction in the number of leads with S-T segment elevation as well as in the sum of S-T segment elevations, but R wave amplitudes did not differ from those in control studies. Calculations of extracellular space, tissue water and cation content revealed a reduced gain of cell sodium ion and loss of cell potassium ion during ischemia after alkali treatment. The latter may account for the S-T segment responses, whereas enhanced ventricular performance may be related to reduced competition of hydrogen ion with calcium ion for binding sites on contractile protein.

Acidosis↗
PubMed1976

Cardiovascular effects of long-term cigarette smoking and nicotine administration.

The nature of the cardiovascular risk in cigarette smokers has not been characterized. To compare the relative effects of long-term smoking and nicotine administration on the cardiovascular system, 18 month old beagle littermates were prepared with a permanent tracheostomy. They were classified into three groups: I, seven control dogs; II, nine dogs that smoked seven cigarettes/day; and III, eight dogs that received an equivalent amount of nicotine. After a period of up to 22 months, the animals were catheterized under anesthesia for assessment of left ventricular function and volumes by indicator-dilution technique. Heart rate, stroke volume, left ventricular end-diastolic pressure and volume and intraventricular conduction times did not differ significantly in the three groups. Left ventricular ejection fraction was 44 +/- 3 percent (mean +/- standard error of the mean) in the control group, 35 +/- 3 percent in the dogs that smoked cigarettes (P less than 0.05) and 27 +/- 3 percent in those given nicotine (P less than 0.01) despite similar values for end-diastolic variables in the three groups. The first derivative of left ventricular pressure (dP/dt) normalized for pre- and afterload was 2.4 +/- 0.2 cm/sec -1 in the control group, 1.41 +/- 0.12 in the cigarette-smoking group (P less than 0.005) and 1.34 +/-0.08 in the nicotine group (P less than 0.01). Although mean aortic pressure was significantly elevated in both the smoking (127 +/- mm Hg) and nicotine (127 +/- 10 mm Hg) groups, there was no significant correlation with the contractility indexes. Reduction of afterload to normal levels did not affect the abnormal ventricular performance. Hypertrophy, inflammation and abnormalities of cell ultrastructures were not present, and myocardial lipid and cation composition were normal. Since interstitial fibrosis was evident in both experimental groups, an alteration of elastic elements may be operative. These cardiovascular abnormalities appear to be predominantly dependent on the nicotine of cigarettes.

Animals↗
PubMed1976

Preclinical cardiomyopathy in chronic alcoholics: a sex difference.

Alcoholic subjects differ in the incidence of cardiomyopathy. Of potential variables, sex may be important since few females are seen with cardiomyopathy, even adjusting for the lower incidence of alcoholism. To examine this question, noninvasive systolic time intervals were measured in 22 males and 14 females of similar age, heart rate, and arterial pressure, without clinical evidence of heart disease or hypertrophy. Duration and intensity of ethanol intake and the interval from last drinking episode were apparently equivalent. In male alcoholics, the left ventricular preejection period and ejection time (PEP/LVET) ratio of 0.410 +/- 0.020 was significantly higher than in the 11 normal males (0.316 +/- 0.007) (P less than 0.001). In female alcoholics, the ratio was 0.322 +/- 0.015, compared to 0.310 +/- 0.01 for 11 normal females, and was significantly less than in the male patients (P +/- 0.001). In addition prolonged intraventricular conduction by high-frequency ECG was more prevalent in the male group. To further ensure equivalency of alcoholism, patients with biopsy-proved cirrhosis were selected. In nine males, PEP/LVET was significantly higher than in the 10 females. Thus, abnormal myocardial function was evident in males but not in females, suggesting that sex is a determinant of the toxic effects of ethanol on myocardium.

Adult↗
PubMed1976

Comparison of the coronary collateral circulation in dogs and baboons after coronary occlusion.

The relevance to man of experimental observations on coronary collateral blood flow (CCBF) in dogs has been questioned. The effect of 2 to 3 hour coronary occlusions in the anesthetized dog and a primate, the baboon, were therefore compared, with CCBF measured by injections of 85Kr distal to occlusion with precordial counting. Before killing, additional isotope was infused to compare inner/outer wall flow distribution and myocardial tissue samples were analyzed for electrolyte content. Effects of nitrates on hemodynamics and metabolism were also compared in dog and baboon. Similar values for CCBF and resistance following occlusions were found in dog and baboon (flow approximately 25 per cent control, calculated resistance increase four- to sevenfold). Greater subendocardial ischemia in both species was indicated by isotope distribution less to the inner wall, but electrolyte changes (k+ less and Na+ greater in the ischemic area compared to nonischemic) were similar transmurally in both species. Hemodynamic responses to nitrate infusion (isosorbide dinitrate) were similar, with increase in CCBF and decrease in resistance. In neither group were inner/outer wall isotope distribution or electrolyte changes influenced by nitrate. The coronary collateral response to occlusion is similar in dog and baboon in terms of both hemodynamics and metabolic changes. After 2 to 3 hours of coronary occlusion some hemodynamic benefit may be demonstrated with nitrates but no metabolic advantage, at least in the central area of ischemia.

Animals↗
PubMed1976

Cardiac conduction abnormalities produced by chronic alcoholism.

While conduction disturbances and arrhythmias are seen frequently in alcoholic cardiomyopathy, the specific relationship of these changes to ethyl alcohol has been unclear. To investigate the long-term effects of ethanol upon cardiac conduction, alcoholism was induced in 11 male mongrel dogs for 7 to 33 (mean 14.4) months by feeding up to 36 per cent of total daily calories as ethanol while adequate nutrition was maintained. His and left bundle branch electrograms in the intact anesthetized animals were recorded along with high-speed, high-frequency ECG's. While resting left ventricular pressures, volumes, and stroke outputs were normal, H-Q time was prolonged in the alcoholic animals drinking for longer than one year (35 +/- 3 msec., normals 26 +/- 1 msec.-P less than 0.001). QRS widening (to 80 +/- 4 msec.) was also evident after one year as compared with normals (62 +/- 2 msec.-P less than 0.001), and both H-Q and QRS alterations correlated with duration of intake. These changes were less after shorter ingestion periods, could not be reproduced in normals by acute ethanol infusion, and were not associated with ventricular hypertrophy, inflammation, or necrosis. No abnormalities of atrial conduction were noted. Morphologic correlates of the conduction abnormalities included accumulation of Alcian Blue-positive interstitial material as well as dilatation and localized swelling of the nonspecialized region of the intercalated discs in ventricular muscle and Purkinje fibers. Thus, prolonged ethanol intake in the absence of evident malnutrition resulted in demonstrable intraventricular conduction abnormalities and morphologic alterations which were related to duration of ingestion, consistent with a cumulative toxic effect of ethanol.

Alcoholism↗
PubMed1976

Evaluation of potassium-43 scintillation images during early myocardial ischemia in an animal model.

To assess the validity of myocardial imaging with potassium-43 (43K) early after the onset of ischemia, the left anterior descending artery was occluded with a baloon tip catheter in 32 intact anesthetized dogs. 99mTechnetium ventriculograms localized the left ventricle. 43K was administered intravenously and serial images were obtained in four views using an Anger camera with a pinhole collimator. The heart was arrested after 60 minutes and removed for imaging and tissue counts to ascertain extracardiac and geometric factors. In normals (group 1) left ventricular images were relatively homogeneous, except for the thin walled apex, both in vivo and in the isolated heart. Equilibration with 43K prior to ischemia (group 2) gave similar images to group 1, associated with a small reduction in tissue count after one hour of ischemia. Group 3 was infused with 43K after initiation of ischemia. Despite a reduction of 43K counts in the ischemic area to less than one-fourth of the nonischemic site (P less than 0.001), demonstration of a "cold area" in vivo was inconstant, occurring in only 34% of studies. Lead shielding did not improve accuracy. In the isolated heart the ability to detect the cold area was improved to 73%. However, when the left ventricle was incised and spread flat, so that low and high activity areas were contiguous rather than superimposed, a widespread area of ischemia was present without exception in the anterior wall. Use of a rectilinear scanner in seven animals failed to improve diagnostic yield; areas of reduced radioactivity were seen at the apex in normals by both techniques. Thus, while detection of low flow areas in the isolated heart is feasible by isotopic imaging early after the onset of ischemia, both extracardiac and geometric factors can contribute to qualitative and quantitative errors in vivo.

Animals↗
PubMed1976

Effect of coronary thrombus age on fibrinogen uptake.

A study was carried out to define the time limits during which an experimental coronary thrombus remains capable of incorporating fibrinogen. 131I-fibrinogen was given to intact anesthetized dogs at different time intervals, up to 67 hours, following the formation of a coronary thrombus by catheter-electrode. Radioactivity of the recovered thrombi as a whole and segmentally divided, was determined following variable time intervals of exposure to circulating fibrinogen and was expressed as thrombus/blood ratio. The results indicate that coronary thrombi formed in a normal coronary vessel remain capable of incorporating fibrinogen for at least eighteen hours, with no significant differences in the segmental distribution of radioactivity. These findings do not support the view that the recovery of isotopic fibrinogen, which was given after the onset of coronary symptoms, in thrombi from patients with myocardial infarction establishes that the thrombus was initiated after the ischemic process.

Animals↗
PubMed1976

Diabetes mellitus and left ventricular function.

Chronic diabetes mellitus can alter left ventricular function independent of vascular effects. On the basis of available morphologic data in human and canine diabetics, alterations of myocardial interstitium may be the basis for this preclinical abnormality. The abnormal function is independent of apparent duration and treatment by diet, insulin, or hypoglycemic agents. It occurs in both sexes and is independent of age. Whether the observed functional abnormality progresses to clinical heart failure may depend on intensification of the underlying pathophysiology of the myocardium or superimposition of complications such as hypertension, obesity, and obstructive disease of the coronary vessels.

Animals↗
PubMed1975

The effect of angiotensin on myocardial contractility.

Previous studies of the effect of angiotensin on myocardial contractility have yielded conflicting results. Possible reasons for the observed disparities include differences in techniques for measuring contractility, in species (dog, cat, and man), in myocardial state (normal or diseased), in preparation observed (heart-lung, isolated heart, papillary muscle, atrial myocardium, intact heart), and in dosage schedule. Moreover, there are no reported studies in the intact human heart, normal or diseased, in which contractility measurements are based on velocity-force relations. To resolve the conflict, left ventricular myocardial contractility was measured using the same expressions for the force-velocity relationship in all subjects. Studies were performed in five normal human subjects, six patients with cardiomyopathy, eight normal mongrel dogs, and six dogs with ischemic myocardial scarring, before and during angiotensin infusions in dosages producing 15--20-mm Hg increases of aortic diastolic pressure. Contractile element velocity at peak, dP/dt (Vce) and the Frank-Levinson contractility index (CyIx), which normalizes Vce for diastolic fiber length, decreased during angiotensin infusion in all groups. The mean decreases (11 to 19) per cent in Vce, 15 to 23 per cent in CyIx, SEM's 4-5 per cent) were significant (P values ranging from smaller than 0.05 to smaller 0.005) in the normal hearts of dogs and man and in the scarred canine hearts, in which preangiotensin Vce and CyIx were normal. In the cardiomyopathy group, in which contractility was depressed before angiotensin, the drug elicited a further decrease in Vce (mean fall 17 plus or minus 7 per cent, P smaller than 0.1) and CyIx (26 plus or minus 8 per cent, P smaller than 0.02). We conclude that, in the intact organism, with a normal myocardium or a diffuse or segmental myocardial disease, the administration of angiotensin results in a depression of contractility.

Alcoholism↗
PubMed1975

Preclinical abnormality of left ventricular function in diabetes mellitus.

Abnormal cardiac muscle function has been reported in experimental diabetes mellitus from this laboratory. To examine left ventricular performance in diabetic patients without clinical evidence of myocardial ischemia or other cardiovascular disease, a noninvasive measurement of the systolic time intervals was carried out. Simultaneous recordings of the electrocardiogram, heart sounds, and carotid pulse were made in 25 diabetic subjects, 20 to 56 years of age, and compared with 37 normal subjects. The diabetic subjects had a shorter left ventricular ejection time, longer pre-ejection period, and a higher ratio of pre-ejection period/left ventricular ejection time (P less than 0.001). The isovolumic time was prolonged (P less than 0.001), while heart rate and arterial pressure were within normal limits. Abnormal function was independent of apparent duration and treatment by diet alone, insulin, or hypoglycemic agents. On the basis of available morphologic data in human and canine diabetes, an alteration of the myocardial interstitium may be the basis for this preclinical abnormality in diabetic patients.

Adult↗
PubMed1975

Ischemic heart failure: sustained inotropic response to small doses of I-epinephrine without toxicity.

As a prelude to a study of severe ischemic heart failure, the therapeutic response of the ischemic ventricle to epinephrine and acetylstrophanthidin in nontoxic doses was determined in 24 intact anesthetized dogs undergoing a first episode of acute regional ischemia. A thrombotic obstruction was produced in the left ventricular dysfunction. The elevation of end-diastolic pressure and reduced stroke volume in control dogs were not significantly altered by administration of strophanthidin. Epinephrine (0.05 mug/kg per min) elicited a significant reduction in end-diastolic pressure and increase in stroke volume. The latter was not attended by an increased incidence of ventricular fibrillation, whereas fibrillation occurred in half of the group given strophantihidin. Thus, the catecholamine was selected to study pump failure. Severe ischemic heart failure was assessed in two groups with scar from previous infarction for up to 4 hours. By 60 minutes of ischemia the increase in end-diastolic pressure and volume and decrease in stroke volume and ejection fraction were comparable in both groups. Thereafter, alternate animals received small doses of epinephrine (0.05 to 0.15 mug/kg per min) with graded increments at 60 minute intervals to counter tachyphylaxis and findings were compared with those in control dogs. Over the subsequent 3 hours, there was progressive deterioration of left anterior descending coronary artery, affecting ventricular function in the untreated group with an increase in end-diastolic pressure from 10 plus or minus 1 to 33 plus or minus 2.4 mm Hg. End-diastolic volume increased by 63 percent; stroke volume and ejection fraction decreased by 48 and 66 percent, respectively. The infusion of epinephrine was attended by a significantly lower end-diastolic pressure of 20 plus or minus 2.5 mm Hg, whereas end-diastolic volume, stroke volume and ejection fraction were restored to control levels after 4 hours of ischemia. Mortality in the untreated group was 62 percent by 4 hours; all seven animals in the treated group survived.

Animals↗